Method for introducing conjugated caps onto molecular fragments and systems and methods for using the same to determine inter-molecular interaction energies

ABSTRACT

A method of introducing conjugated caps onto molecular fragments is described. A first molecule may be decomposed or cut into molecular fragments. Molecular caps may then be introduced in the form of conjugated caps onto the molecular fragments at the decomposition points to form molecular portions. The interaction energy between the molecular portion and a second molecule can then be calculated. This scheme, termed molecular fractionation with conjugated caps, makes it possible and practical to carry out full quantum mechanical (ab initio) calculation of intermolecular interaction energies involving molecules, such as proteins or other biological molecules.

This application claims benefit of U.S. Provisional Patent ApplicationSer. No. 60/463,753, filed Apr. 17, 2003, the disclosure of which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to a method of introducing conjugated caps ontomolecule fragments. After the molecule portions have been capped, theintermolecular interaction energy between the decomposed molecule and asecond molecule can be calculated using the molecular portions.

BACKGROUND OF THE INVENTION

A grand challenge in computational chemistry and biology is the accuratequantum mechanical calculation of interaction energies for molecules,especially larger biological molecules such as proteins. Due to a largernumber of atoms, standard full quantum mechanical or ab initiocalculation of intermolecular interaction energy is beyond computationalreach. Currently, most theoretical studies of biological moleculesemployed classical force fields that are built on pair-wise atomicinteraction potentials. Despite the success of classical force fieldmethods in many applications, they still have significant limitationsand quantum mechanical calculations of interaction energies are oftenrequired, e.g., in studying enzyme reactions.

Recently, a popular approach to applying quantum mechanical calculationto biological molecules is the hybrid quantum mechanical/molecularmechanical (QM/MM) approach in which one combines quantum mechanicalmethods with molecular force fields for large molecules. In this hybridQM/MM approach, one employs quantum mechanical or ab initio methods suchas Hartree-Fock (HF) or density functional theory (DFT) methods to treata small subsystem while using molecular force fields to treat the largerpart of the system such as solvent molecules. However, the QM/MMapproach cannot provide a proper description of the interface betweenthe QM and MM regions because QM and MM approach are inherentlyincompatible with each other.

Currently, there are two basic approaches to solving this problem: thelink atom approach or its variants and the local self-consistent field(LSCF) method, both of which use strictly localized bond orbitals forthe bonds between QM and MM atoms. Despite the progress in theseapproaches in solving the interface problem, some artifacts still existsin applications of QM/MM methods.

Another approach for calculation of large systems is the linear scalingapproach in which the large system is divided into small subsystems andthe calculation of the large system is performed for each subsystemindividually. The linear scaling approach is based on the local propertyof the interaction because the effect of energy perturbation in one areais generally localized within its vicinity and decays rapidly going awayfrom it. In this approach, the divide-and-conquer (DAC) and similarmethods are commonly employed in theoretical calculations. Althoughthese methods scale linearly with the size of the 2 system, applicationsare currently limited to calculations using semi-empirical methods forproteins. Ab initio calculations of biological molecules using HF or DFTmethods are not feasible.

There is thus a need for developing a practical and efficient fullquantum mechanical method for calculating interaction energies ofmolecules such as proteins. This invention answers that need.

SUMMARY OF THE INVENTION

A first embodiment of this invention relates to a method of introducingconjugated caps onto molecule fragments. In this method, a firstmolecule is provided. The molecule is then decomposed into two or moremolecular fragments. One or more pairs of conjugated caps, which containa first cap member and a second cap member, are introduced at one ormore location in the molecule creating a plurality of molecularportions. Each molecular portion contains a fragment of the firstmolecule and at least one of the first and second cap members of theconjugated caps. A further embodiment uses the molecular portions tocalculate the interaction energy between the first molecule and a secondmolecule.

A second embodiment of this invention relates to a computer-readablemedium having stored instructions for calculating inter-molecularinteraction energy between two molecules. The stored instructionscomprise instructions for (a) providing a first molecule; (b)decomposing the molecule into two or more molecular fragments; and (c)introducing one or more pairs of conjugated caps having a first memberand a second cap member at one or more locations in the molecule tocreate a plurality of molecular portions. Each molecular portioncontains a fragment of the first molecule and at least one of the firstand second cap members of the conjugated caps.

A third embodiment of this invention relates to a system for calculatingintermolecular interaction energy. The system contains (a) a molecularrepresentation module that provides a first molecule; (b) a moleculardecomposing module that decomposes the molecule into two or moremolecular fragments; and (c) a molecular cap pair introduction modulethat introduces one or more pairs of conjugated caps having a firstmember and a second cap member at one or more locations in the moleculeto create a plurality of molecular portions. Each molecular portion inthe molecular representation contains a fragment of the first moleculeand at least one of the first and second cap members of the conjugatedcaps.

A fourth embodiment of this invention relates to a composition. Thecomposition contains a molecule having a plurality of units and aplurality of pairs of conjugated caps having a first cap member and asecond cap member. Each of the plurality of pairs of conjugated caps isinserted between two of the units under conditions effective tosubstantially preserve the properties of a chemical bond being cut toinsert the pair of conjugated caps. The first cap member substantiallymimics the electronic effect of the units of the molecule on a firstside of the pair of conjugated caps and the second cap membersubstantially mimics the electronic effect of the units of the moleculeon a second side of the pair of conjugated caps.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of an extended tripeptide and thelocations of the cuts where conjugated caps are introduced.

FIG. 2 is a block diagram of a computer system for practicing the methodof the preferred embodiment.

FIG. 3 is a flowchart depicting the method steps of the preferredembodiment.

FIGS. 4A-4C represent the all-atom figure of three peptides: (a) Gly-Glytripeptide; (b) Me-His-Ser-Me dipeptide with both terminals replaced bymethyl groups; and (c) Gly-Ser-Ala-Asp-Val pentapeptide.

FIG. 5 represents the coordinate system with the origin centered on thecenter-of-mass of Gly-Ser-Ala-Asp-Val. The interaction potential iscalculated for the water molecule approaching the center-of-mass of thepeptide from specified spherical angles (θ, φ).

FIG. 6 represents a comparison of ab initio and DFT calculations fortriglycine/water interaction potential between the MFCC and FS (fullsystem) calculations using different basis sizes. The approachingspherical angles of water are fixed at (90, 0).

FIGS. 7A-7F represent one-dimensional (1D) potential curves fortriglycine/water interaction at various directions obtained by MFCC andFS calculations using DFT B3LYP/6-31G. The solid line with dots are theFS result, dotted lines are MFCC results and dashed lines are theresults from AMBER force fields.

FIGS. 8A-8F represent 1D potential curves for Me-His-Ser-Me/waterinteraction at various directions obtained by MFCC and FS calculationsusing DFT B3LYP/6-31G. The solid line with dots are the FS result andthe dotted lines are MFCC results.

FIGS. 9A-9F represent 1D potential curves for Gly-Ser-Ala-Asp-Val/waterinteraction at various directions obtained by MFCC and FS calculationsusing HF/3-21G. The solid line with dots are the F result, the dottedlines are MFCC results, and the dashed lines are the results from AMBERforce fields.

FIGS. 10A-10F represent 1D potential curves forGly-Ser-Ala-Asp-Val/water interaction at various directions obtained byMFCC and FS calculations using DFT B3LYP/6-31G. The solid line with dotsare the FS result and the dotted lines are MFCC results.

FIG. 11 represents illustrative interaction paths between a watermolecule (indicated by arrows) and the fixed structure HIV-1 gp41protein. The distances is defined between the two atoms on both ends ofthe arrows except for FIG. 11A where the distance is defined between theoxygen atom of the water and the center-of-mass of gp41.

FIGS. 12A-12D represent the 1D (one-dimensional) gp41-water interactionpotential curves as a function of interaction path defined in FIG. 9.The solid circles are the results of ab initio calculations and dottedlines are the results from AMBER force field. The B3LYP/6-31G andMP2/6-31G results are denoted, respectively, by open circles and opensquares in (B) and (D).

DETAILED DESCRIPTION

The first embodiment of this invention relates to a method ofintroducing conjugated caps onto molecular fragments. A first moleculeis provided, and then decomposed into two or more molecular fragments.Pairs of conjugated caps, containing a first cap member and second capmember, are introduced onto the molecular fragments at eachdecomposition point in the molecule. The pairs of caps are introduced ina manner that, after introduction, each molecular portion contains amolecule fragment and at least one cap member. FIG. 3 is a flowchartdepicting the method steps of the preferred embodiment.

When the molecule has been decomposed or cut, the individual pieces ofthe molecule are referred to as molecular fragments, whereas, after themolecular fragments have been capped, they are referred to as molecularportions.

In the first step, a first molecule is provided. Preferably, themolecule is provided electronically, such as on a computer or othersystem that has the capability of executing modeling software. Othermeans capable of providing a molecular, graphical, or mathematicalrepresentation of the molecule may also be used. For instance, themolecule may be provided as data plotted on a coordinate system or otherstructural-information system that describes the molecule. Downloadinginformation off the internet that describes the molecule, such ascoordinate data about the molecule, is an example of providing themolecule.

As is well known in the art, there are many different parties providingelectronic downloadable information on molecules, such as the proteindatabase bank (pdb). The protein database bank website, as well as othersites, are able to provide the molecule as a set of coordinates, witheach atom of the molecule having distinct coordinates. A sample set ofx, y, and z coordinates obtained from the protein database bank forprotein gb41 is provided below:

ATOM 1 N 26.801 20.370 −22.607 ATOM 2 H1 27.720 20.763 −22.465 ATOM 3 H226.112 21.023 −22.263 ATOM 4 H3 26.740 20.022 −23.553 ATOM 5 CA 26.67219.167 −21.736 ATOM 6 HA 25.835 19.339 −21.059 ATOM 7 CB 26.403 17.903−22.573 ATOM 8 HB 25.490 18.038 −23.152 ATOM 9 CG2 27.574 17.662 −23.520ATOM 10 1HG2 28.488 17.526 −22.941

The coordinates may then be graphically displayed using a plottingprogram that displays a molecular image of the molecule in a format suchas that shown in FIGS. 4A-4C or FIG. 5. Any VRML compliant program orother program, such as Rasmal™, can be used to perform this function.While it is sometimes easier to conceptualize the features of themolecule when it is visually displayed, it is not necessary to displaythe molecule for the purposes of this invention.

Other software and hardware that has the capability of generatingmolecules in electronic format or on a computer-readable medium areacceptable. Additionally, other non-electronic means of providing themolecule known to those of skill in the art may also be used; e.g.,providing one or more physical models of the molecules.

The first molecule may be selected from any molecule known in the art.Preferably, the first molecule is a polyatomic species. Larger moleculessuch as materials, proteins, polymers, DNA, or RNA, are typically usedas the first molecule because the calculations relating tointermolecular interaction energies are most useful for these types ofmolecules. However, the first molecule may also be a smaller molecule,such as an ion, a water molecule, an inorganic molecule, an organicmolecule, a drug molecule, or a biological molecule.

The first molecule is then decomposed into two or more molecularfragments. The molecule may be decomposed, i.e., cut, by any means knownin the art. Preferably, the molecule is decomposed electronically, suchas on a computer or via a molecular processing system. When the moleculeis provided by means of structural information describing the molecule,the decomposition step may be effected by cutting the molecule into thedesired molecular fragments based on the structural description. Forinstance, if the molecule is represented as a set of coordinates, witheach atom of the molecule having distinct coordinates, the molecule canbe decomposed by splitting the molecule at the coordinates correspondingto the decomposition points. A set of coordinates may be inputted intothe system to designate the decomposition point or a molecular fragmentoccupying a set of coordinates.

It is also within the capabilities of a skilled artisan to create asoftware program that decomposes a given molecule when specificdecomposition points are provided. Appended to this disclosure is anexample of source code of an executable computer program that can beused to decompose a molecule provided by means of a coordinate system.Different programs may be used and may be preferred depending on thehardware a user has at his or her disposal, the mechanism for providingsuch a program, and other factors determinable through routineexperimentation.

Cuts should be made across covalent bonds, preferably across covalentbonds that are single bonds. However, the cuts may be made across alltypes of bonds, including double and triple bonds. Cuts may also be madeacross ring structures, such as benzene rings. Since the amount of cutscorrespond with amount of desired molecular fragments, a skilled artisanmay choose to make many cuts or only a few cuts in the moleculedepending on how many molecular fragments is deemed necessary ordesirable. The amount of cuts and desired molecular fragments depends onthe size of the molecule, the configuration of the molecule, the purposeof the cuts, and other factors that may be determined by routineexperimentation by those of skill in the art.

When discussing the decomposition of the molecule, it is useful to lookat a theoretical example, such as the decomposition of a proteinmolecule P with N amino acids. This molecule can be represented at agiven (fixed) structure as:P=nA ₁ −A ₂ −A ₃ − . . . −A _(N) cwhere Ai(i=1, . . . , N) are individual amino acid units, n is theN-terminal of the proteinn=NH₃ ⁺(NH₂)for the charged (neutral) N-terminal of the protein. The C-terminal ofthe protein is represented asA_(N)C=R_(N)CHCOO⁻(R_(N)CHCOOH)for the charged (neutral) C-terminal. FIG. 1 shows the sequence of ageneral 3-amino acid peptide (tripeptide) with charged terminals.

As shown in FIG. 1, the cuts could take place between the carbon andnitrogen bonds for the tripeptide, as illustrated in that figure. Inthis case, the point of the cuts between the carbon and nitrogenrepresent the decomposition points for that molecule. Of course, cuts donot have to take place across all covalent bonds in the molecule. Forinstance, the cuts could also be made between the peptide bond forcertain advantages or conveniences. As longs as the cuts are made in amanner that a cap may be introduced onto the molecule fragment at thedecomposition point, it is not critical where the cuts are made in themolecule or how many cuts are made in the molecule. For largermolecules, many cuts will typically be made, resulting in many molecularfragments. For smaller molecules, only a few, perhaps only a single cut,may be needed.

After the molecule has been cut, at least one pair of caps that areconjugate to each other is introduced at one or more points in themolecule. Caps may be introduced onto the molecular fragment by anymeans known in the art. Preferably, the caps are introduced byelectronically inserting the molecular cap at the decomposition pointsin the molecule. A molecular processing system may be used to introduceor insert the caps.

For molecules provided by means of structural information describing themolecule, the molecular caps may be introduced based on structuralinformation. If the molecule is represented by a set of coordinatesidentifying the atoms in the molecule, and decomposed at certainidentified decomposition points, molecular caps may be introduced ontoeach molecular fragment by entering the coordinates of the atoms of thecap member at the desired composition point. The coordinates may then beconverted to a visual representation through various modeling programs,such as VRML compliant programs to check the accuracy of the capintroduction.

Each pair of caps contains two cap members, a first cap member and thesecond cap member. Pairs of conjugate caps are introduced into themolecule at each decomposition point. One cap member is introduced ontoeach molecule fragment so that the pairs of conjugate caps are alignedadjacent to one another. For illustrative purposes, the caps may bedesignated C^(i) _(ap) and C^(i)*_(ap), where i equals 1, . . . N. Forexample, in FIG. 1, cap C¹ _(ap) is used to terminate the right end ofmolecule fragment nA₁ at the first decomposition point, while itsconjugated cap C¹*_(ap) is employed to terminate the left end ofmolecule fragment A₂; similarly, cap C² _(ap) is employed to terminatethe right end of molecule fragment A₂ at the second decomposition point,while its conjugate cap C²*_(ap) is used to terminate the left end ofmolecule fragment A₃c.

The caps should be introduced onto the molecule fragments so that eachmolecular portion will contain the molecule fragment and at least onecap member. In FIG. 1, the left-hand molecule portion contains moleculefragment nA₁ and cap member C¹ _(ap); the middle molecule portioncontains molecule fragment A₂ and cap members C¹*_(ap) and C² _(ap); theright-hand molecule portion contains molecule fragment A₃c and capmember C²*_(ap). Thus, the right and left-hand molecule portions containa molecule fragment and one cap member, while the middle moleculeportion contains a molecule fragment and two cap members.

Caps are atoms or radicals that bond with the fragment of the moleculethat has been severed at the decomposition point. The caps serve twopurposes. First, they preserve the property of the valence bond beingcut. The caps should preserve this property as closely as possible,serving a similar purpose as the link-atom in the QM/MM approachdiscussed above. Second, the caps should mimic as much as possible theeffect of the original molecular part being cut away from the remainingfragment. For example, in FIG. 1, C¹ _(ap) should closely represent theelectronic effect of everything to the right side of the firstdecomposition point, and C¹*_(ap) should closely represent theelectronic effect of nA₁ on the A₂ unit.

One skilled in the art may choose from various possible molecular capswhen choosing suitable molecular caps using the criteria describedabove. This, of course, also applies for molecular caps C¹ _(ap) andC¹*_(ap). In FIG. 1, the first cap C¹*_(ap) could be NH⁺ ₃ (NH₂) for thecharged (neutral) N-terminal. Other caps placed in the middle of themolecule may be, for exampleC^(i) _(ap)=R_(i+1)C_(α)H₂for (i=1, . . . , N−1). The right-end (C-terminal) cap is simply definedasA_(N)C^(N) _(ap)=R_(N)C_(α)HCOO⁻(R_(N)C_(α)HCOOH)for the charged (neutral) C-terminal (cf. FIG. 1). The correspondingconjugate caps are thenC^(i)*_(ap)=NH₂for (i=1, . . . , N−1).

After a molecule has been decomposed and capped with conjugated caps tocreate a plurality of molecular portions, the molecular portions may beused to measure intermolecular interaction energy. Intermolecularinteraction energy calculations attempt to measure the transfer ofenergy between two given molecules. When calculating intermolecularinteraction energy, at least two molecules are provided. In the methodof this invention, the second molecule may be any molecule that onewishes to use in comparison to or in reference to the first molecule.Typically, the second molecule is a smaller molecule, such as an ion, awater molecule, an inorganic molecule, an organic molecule, a drugmolecule, or a biological molecule. Water is perhaps the most commonsecond molecule used in basic intermolecular-interaction-energycalculations. When calculating intermolecular interaction energies forproteins and peptides, drug molecules and biological molecules representpreferred second molecules because of the practical benefit associatedwith protein inhibitors in drug discovery. However, any molecule may beused as the second molecule, included those listed as acceptablemolecules for the first molecule.

Once the first molecule has been decomposed into molecular fragmentshaving conjugate caps, the intermolecular interaction energy between thefirst molecule and a second molecule can be calculated. Whileinteraction energies may now be calculated, the use of molecules havingmolecular portions with conjugated caps is not limited tointeraction-energy calculations. For instance, molecules havingmolecular portions with conjugated caps may also be used forcalculations for determining the electron density of the molecules,dipole moment, electrostatic potential, and intra-molecular energy.

In this calculation, the interaction energy is determined between eachof the molecular portions in the first molecule and the second molecule.Interaction energy may be calculated using the well known full quantummechanical or ab initio calculations. However other interaction energycalculations known to those of skill in the art may also be used.Preferably, software or hardware is used to make the calculations. TheGaussian™ software has the capability of performing full quantummechanical interaction energies. This program may be obtained atGaussian's website. Each of these interaction energies is then added orsummed together to provide a total interaction energy of the molecularportions.

Likewise, the conjugated cap interaction energy may be determined foreach pair of conjugated caps and the second molecule. The sameinteraction energy calculation used for determining the interactionenergies of the molecular portions, e.g., the full quantum mechanical orab initio calculations, should also be used for determining theinteraction energies of the conjugated caps. The total interactionenergy of the conjugated caps may then be determined by summing togetherall the conjugated cap interaction energies.

Once the total interaction energy of the molecular portions and thetotal interaction energy of the conjugated caps have been calculated,the intermolecular interaction energy between the first molecule and thesecond molecule can be determined by subtracting the total interactionenergy of the conjugated caps from the total interaction energy of themolecular portions.

In a preferred embodiment, a molecular interaction energy system is usedto sum together the molecular portion and conjugated cap interactionenergies and a interaction adjustment system is used to subtract thetotal interaction energy of the conjugated caps from the totalinteraction energy of the molecular portions.

The calculation of interaction energies with this process, termedmolecular fractionation with conjugate caps (MFCC) method, aims toprovide accurate molecular interaction energies for molecules,especially large polyatomic molecules like protein, by means of fullquantum mechanical electron structure calculations. By breaking themolecule into individual amino fragments that are properly capped, theinteraction energy of a second molecule with the first molecule at agiven structure can be obtained by proper combination of the interactionenergies between the second molecule and individually capped proteinfragments of the first molecule. The extra interactions between thesecond molecule and the introduced caps are canceled by subtracting theinteraction between the molecule and the artificial molecules formed byconjugate caps. The MFCC scheme is particularly suitable for obtainingaccurate ab initio interaction energies between a protein with a fixedstructure and another molecule. The MFCC scheme is highly efficient forab initio calculation and scales linearly with the size of the firstmolecule. In addition, since the interaction energies between the secondmolecule and individual molecule fragments of the first molecule can becalculated independently, it is particularly suitable for calculation onmulti-node computer clusters.

The basic approach of to the calculation interaction energy using MFCCis based on the hypothesis that first-molecule/second-moleculeinteraction energy is localized. While not wishing to be bound by thistheory, it is believed that it is possible to accurately represent theinteraction energy between the molecules as a sum over interactionsbetween the second molecule and individual fragments of the firstmolecule. In this approach, the interaction of the second molecule withthe first molecule involving simultaneous multi-fragment interactionsare assumed to be negligible.

Computing systems may be utilized to run the interaction energycalculations. Different computing systems or devices may be used foreach calculation, or a single computing system may be used to run allthe calculations together. It may be preferable to use differentcomputing system or device for each molecular portion. For example, afirst computing system may be used to calculate the interaction energybetween a first molecular portion and the second molecule, a secondcomputing system may be used to calculate the interaction energy betweena second molecular portion and the second molecule, and additionalcomputing systems may be implemented for each additional molecularportion. More than one computing system or device may also beimplemented for each portion of the molecule. The calculations may beperformed on parallel or multi-processor computers or other systemsknown in the art.

FIG. 2 illustrates computer system 100 in accordance with a preferredembodiment that can be used to accomplish the methods of the invention.Computer system 100 can include a variety of devices and can be embodiedin a personal computer, workstation, or the like. The various devicescan be coupled in any manner, such as over a LAN, WAN, or through otherchannels. Computer system 100 includes user interface (UI) 100 whichserves to provide all communications and interactions between computersystem 100 and a user in a known manner. UI 100 can include a displayand a keyboard or other input device. Further, UI 100 can include anynecessary software and/or hardware interfaces for effecting theinterface between the user and system 100 in a known manner. Forexample, UI 100 can include software to implement the standard WINDOWS™user interface.

Computer system 100 also includes processor 120, which can be any typeof known processor, such as a PENTIUM IV™, POWERPC™, or other processor.Processor 120 executes instructions stored as software code in memorydevice 130 and/or other memory devices. Memory device 130 includes acomputer readable media, such as a hard disk, a CD, a DVD, a floppydisk, or any other type of media for storing computer readableinstructions. Instructions are read from memory device 130 in a knownmanner to execute the instructions on processor 120. Of course, therecan be other instructions, such as an operating system or the like, tofacilitate execution of instructions stored on memory device 130. Also,memory device 130 can be constituted of plural devices or a singledevice.

Memory device 130 includes molecule generation module 132 which providesinstructions for selecting/generating, i.e., providing, a molecule inthe manner described above. For example, molecule generation module 132can include known electronic downloadable databases, such as the proteindatabase bank. Memory 130 also includes molecule decomposing module 134for accomplishing the decomposing step described above. Moleculedecomposing module 134 can also include program code designed todecompose molecules, such as the program code appended to thisdisclosure. Similarly, cap introduction module 136 includes instructionsfor accomplishing the cap introduction step described above. This alsocan be accomplished using the same or different program code designed todecompose the molecule. Finally, energy calculation module 138 includesinstructions for calculating the intermolecular interaction energy asdescribed above. The programming steps required for accomplishing energycalculation module 138 are well within the ability of a skilledprogrammer in light of the functional disclosure provided herein. Energycalculation module 138 can include energy calculation software such asthe programs produced by Gaussian™.

The second embodiment of this invention relates to a computer-readablemedium, such as the medium of storage device 130, having storedinstructions for calculating the intermolecular interaction energybetween two molecules. When the instructions are executed by at leastone processor, the execution causes the processor to perform the stepsof (a) providing a first molecule; (b) decomposing the molecule into twoor more molecular fragments; and (c) introducing one or more pairs ofconjugated caps having a first member and a second cap member at one ormore locations in the molecule to create a plurality of molecularportions. Each molecular portion contains a fragment of the firstmolecule and at least one of the first and second cap members of theconjugated caps.

The computer-readable medium may also include instructions forcalculating the intermolecular interaction energy between the firstmolecule and a second molecule. The processor may perform this functionin addition to the functions described above during the same execution.The calculation of the interaction energy is the same as that describedabove in the first embodiment of the invention.

The third embodiment of this invention relates to a system forcalculating intermolecular interaction energy. The system contains (a) amolecular representation module that provides a first molecule; (b) amolecular decomposing module that decomposes the molecule into two ormore molecular fragments; and (c) a molecular processing module thatintroduces one or more pairs of conjugated caps having a first memberand a second cap member at one or more locations in the molecule tocreate a plurality of molecular portions. Each molecular portion in themolecular representation contains a fragment of the first molecule andat least one of the first and second cap members of the conjugated caps.

The system for calculating intermolecular interaction energy may be acomputer system. However, other systems that would perform similarfunctions are envisioned. A first molecule may be provided in the form amolecular, graphical, or mathematical representation. An example of amathematical representation is a molecule defined by a set ofcoordinates (x, y, z), wherein each atom of the molecule occupies adistinct location in the coordinates. Molecular processing systems ormodules perform the other functions of decomposing the molecule,introducing conjugate caps onto the molecule fragments, and determiningor calculating the interaction energies. Utilizing molecular, graphical,or mathematical representations and molecular processing modules allowsfor the process to be performed electronically, which is the preferredmeans of execution.

A fourth embodiment of this invention relates to a composition. Thecomposition contains a molecule having a plurality of units, and aplurality of pairs of conjugated caps having a first cap member and asecond cap member, wherein each of the plurality of pairs of conjugatedcaps has been inserted between two of the units under conditionseffective to substantially preserve the properties of a chemical bondbeing cut to insert the pair of conjugated caps. The first cap membersubstantially mimics the electronic effect of the units of the moleculeon a first side of the pair of conjugated caps and the second cap membersubstantially mimics the electronic effect of the units of the moleculeon a second side of the pair of conjugated caps. The function of the capmembers is discussed above in the disclosure relating to the selectionof the cap members.

The composition may be formed by the methods described above, i.e., themolecule may be provided, decomposed, and have conjugated capsintroduced onto the molecule fragments. This forms a composition whereinthe molecule contains a plurality of units that are separate from oneanother.

Alternatively, the pairs of conjugated caps may be fused or otherwiselinked to one another to attach the molecular portions to one another informing the composition. Since each cap member is a radical that liesadjacent to its conjugate, the conjugate cap members may fuse or formwith each other through processes well known in the art. When the unitsare fused or linked together, the molecule can become a singlecontinuous composition.

While each of the four embodiments described above may be used todetermine the intermolecular interaction energy between two molecules,the steps of providing a molecule, decomposing the molecule, andintroducing conjugated caps onto the molecule fragments may also be usedto determine electron density, dipole moment, electrostatic potential,and other calculations. The determination of the electron density p,dipole moment d, and electrostatic potential Φ follows essentially thesame method steps as that for intermolecular energy disclosed above.

Interaction Energy Calculations using a Protein Molecule

This calculation of molecular fractionation with conjugated caps may beexpressed abstractly using the protein molecule P with N amino acidsexample discussed above. Using V(M-P) to denote the interaction energybetween the molecule M (the second molecule) and the protein P (thefirst molecule) with N amino groups, the above fractionation scheme isused to represent V(M-P) byV(M−P)=ΣV(M−C ^(i−1)*_(ap) A _(i) C ^(i) _(ap))−ΣV(M−C ^(i)*_(ap) C ^(i)_(ap))  (1)The first term V (M−C^(i−1)*_(ap)A_(i)C^(i) _(ap)) in Eq. (1) representsthe interaction energy between the molecule M and a capped proteinfragment C^(i−1)*_(ap)A_(i)C^(i) _(ap) where both ends of the fragmentsA_(i) are capped with covalent bonds. The second term in Eq. (1) is theinteraction between the molecule M and an artificial molecule formedfrom conjugate caps Am_(i)=C^(i)*_(ap)−C^(i) _(ap). The calculatedinteraction energies are normalized by subtracting out the values atsome asymptotic geometry. The geometries of the cap atoms are keptexactly the same in the calculation of both interaction energies in Eq.(1) to ensure that the artificial interactions between the molecule Mand the caps are canceled. The energy given in Eq. (1) describes theproper inter-molecular energy between the protein P with a fixedstructure and the molecule M; it does not give the correct internalenergy of the protein itself.

Using Eq. (1), the interaction energy between a protein P and a moleculeM can be obtained by simple summation over individual interactionenergies between the molecule and the capped protein fragments that canbe obtained by ab initio calculations such as HF, DFT or even higherlevel quantum chemistry methods. Obviously, the method scales linearlywith the size of the protein. Since the calculation of the individualinteraction energy in Eq. (1) is independent of each other, the methodcan be easily parallelized and is thus especially suitable for quantumcalculation of interaction energies between proteins and, for example,drug molecules. However, the interactions between proteins and othermolecules may easily be obtained using this method. Additionally, themethod may be applied to other materials besides proteins, such aspeptides, polymers, DNA, and RNA.

The conjugate caps can then be coupled to form artificial molecularspecies whose interaction with the external molecule will be calculatedto cancel out the artificial molecular interaction with individual caps.Thus the calculation of the original interaction energy between themolecule M and the protein P can be replaced by calculation ofinteraction energy between molecule M and individual protein fragments.The two protein fragments whose interactions with the molecule need tobe calculated are the capped protein fragments having the molecularformulaC^(i−1)*_(ap)A_(i)C^(i) _(ap)=NH₂R_(i)C_(α)HCOHNR_(i+1)C_(α)H₂and the coupled caps having the molecular formulaC^(i)*_(ap)C^(i) _(ap)=NH₂R_(i+1)C_(α)H₂Since these fragments are relatively small molecules, the interactionenergy between the M molecule and these small fragments can becalculated by ab initio methods with high efficiency. Since theseindividual interaction energies are calculated independent of eachother, one can easily perform desired ab initio calculations on parallelor multi-processor computers to achieve greater real-time throughput.

The atomic positions of the cap atoms should be exactly the same as thatof the cutoff protein parts replaced by the caps. This avoids thepossible artifacts due to the placement of atoms in empty space ofconfiguration.

EXAMPLES

The following examples make reference to the figures and resultsproduced in those figures. The following examples and numerical testsare intended to illustrate, not limit, the invention.

The above approach has been tested on a number of peptides interactingwith a water molecule and the results of calculations are compared tothe full system (FS) ab initio calculation. Three different peptideswere chosen, as shown in FIGS. 4A-C. The first peptide is composed ofthree glycine (Gly-Gly-Gly) with charged terminals as shown in FIG. 4A.This peptide has a stretched structure whose energy was not optimized.The second peptide is composed of two amino acids but both ends arecapped with the methyl group, i.e., Me-His-Ser-Me as shown in FIG. 4B.The structure of this peptide has been optimized using AMBER forcefield. The third example is a five-base peptide Gly-Ser-Ala-Asp-Val (SEQID NO. 1) whose structure has also been optimized using the force field.The interaction energies between these three fixed-structure peptidesand a water molecule in gas phase were calculated. The MFCC results werecompared with the corresponding full system ab initio calculations. Allab initio calculations were reported using the Gaussian98 package.

No geometry optimization was done to find minimum energy structures ofthe peptide/water complex. Instead, different geometries along which thewater molecule approaches the peptides were selected. FIG. 5 shows thecoordinate system in which the origin of the space-fixed coordinatesystem is at the center-of-mass of the Gly-Ser-Ala-Asp-Val peptide whosegeometry is frozen. The water molecule approaches the center fromdifferent spherical angles (θ, φ). Similar coordinate systems are usedfor the other two peptides. To minimize the number of coordinatechanges, the water molecule stays rigid with its orientation shown inFIG. 5. along the potential curve to be calculated.

FIG. 6 shows ID potentials from ab initio calculations for thetriglycine/water interaction in which the water molecule approaches themass center of the peptide along the spherical angel (90, 0). In FIG. 6,the MFCC results calculated using HF and DFT methods with differentbasis sets were compared with the corresponding full system ab initiocalculations. The results in FIG. 6 shows that although there aresizable differences among different ab initio calculations withdifferent methods and different basis sets, the MFCC results are inexcellent agreement with the corresponding FS calculations across theboard. For example, the HF calculation with a 3-21G basis set gives aminimum energy which is about 5 kcal/mol lower than that calculatedusing a 6-31G basis set. The results from DFT/B3LYP calculations using6-31G and 6-31G* are very close to each other and lie somewhere betweentwo sets of HF calculations. However, in all four sets of calculations,the MFCC results are in excellent agreement with that from thecorresponding FS calculations.

More results of calculations for the triglycine/water system atdifferent geometries are shown in FIGS. 7A-F. Here the DFT B3LYP/6-31Gmethod has been used for all ab initio calculations shown in FIGS. 7A-Fin both MFCC and full system calculations. In all the six geometrieswith different approaching spherical angles of water toward peptide, theMFCC results are in excellent agreement with the full systemcalculations, both in structures and energies of the interactionpotential. The largest errors between the MFCC and full system ab initiocalculations are less than 0.5 kcal/mol in FIGS. 7A-F.

The interaction energies obtained from AMBER force fields fortriglycine/water system at the same geometries are also shown in FIGS.7A-F. As shown, the force field gives some reasonable minimum energypositions at these geometries. However, the force field does not giveaccurate energies. For example, in the potential curve with thespherical angle (90, 0) in FIGS. 7A-F, the minimum energy given by theforce field is only about 7 kcal/mol compared to the ab initio energy of13 kcal/mol. In another potential with the approaching angle of (120,60) in FIGS. 7A-F, the well depth given by the force field is only about0.3 kcal/mol compared to the ab initio calculation of 2.9 kcal/mol.Similar comparisons are seen for other potential curves in FIGS. 7A-F.Thus for the triglycine/water interaction, the force field generallygives energy minimums much higher than ab initio calculations.

For the second system of Me-His-Ser-Me in FIGS. 8A-F the dipeptideHis-Ser has two methyl groups at the ends. The interaction potentialenergy curves are calculated for various approaching spherical angles ofthe water molecule toward the peptide. The comparison between the MFCCand full system calculations at B3LYP/6-31G level is given in FIGS.8A-F. The results in FIGS. 8A-F show that both the structures andenergies from the MFCC calculation are in excellent agreement with theresults from the full system calculation. Even very shallow wells areaccurately reproduced by the MFCC calculation. As shown in FIGS. 7A-F,the approaching angle of water at (130,10) exhibiting a well of lessthan 1 kcal/mol is accurately reproduced by the MFCC calculation. Bothattractive and repulsive potentials are correctly reproduced by the MFCCcalculation.

The third system tested is a relatively larger peptide with five aminoacids having the sequence: Gly-Ser-Ala-Asp-Val (SEQ ID NO. 1) withcharged terminals. This pentapeptide was specifically chosen to includeall three types of side chains: the polar (Ser), nonpolar (Ala and Val)and charged (Asp) side chains and glycine (Gly). In addition, both theN- and C-terminals are charged. This pentapeptide/water system has atotal number of 62 atoms. FIGS. 9A-F shows various 1D potential curvesgenerated from ab initio calculations at the HF/3-21G level fordifferent approaching angles of water. The agreement between the MFCCand full system ab initio calculations is generally very good for allpotential curves as shown in FIGS. 9A-F. Both the structures of thepotential curves and energies are quite well reproduced by MFCCcalculations in all six cases. The largest deviation in energy from thefull system calculation is about 0.5 kcal/mol in FIGS. 9A-F for theapproaching angle of (140, 200). Even the structure of a small bump ofabout 0.4 kcal/mol for the water approaching angle (30, 240) isfaithfully reproduced as shown in FIGS. 9A-F. For purpose of comparison,the potential curves obtained from the force field are also shown inFIGS. 9A-F. Similar to the results of the triglycine in FIGS. 7A-F, theforce field generally gives too shallow wells relative to ab initiocalculations. Next, the DFT calculations were performed at theB3LYP/6-31 G level for the same geometries of pentapeptide/water system;the results are shown in FIGS. 10A-F. Although there are differences inresults between HF/3-21G and B3LYP/6-31G calculations, the MFCCcalculation can reproduce the corresponding result of full systemcalculations using the same level of ab initio methods quite accuratelyas shown in FIGS. 10A-F.

FIGS. 11A-D shows positions of part of the gp41 atoms surrounding thewater molecule shown with arrows. The structure of gp41 is obtained fromPDB (protein data bank) and is fixed throughout the calculation. The abinitio calculation of the protein-water interaction is performed togenerate 1D potential curves by moving the water molecule with fixedorientation along the direction indicated by the arrows as indicated inFIGS. 11A-D. Four different interaction paths were chosen as shown inFIGS. 11A-D. These paths generally involve some form of hydrogen bondingor attractive interactions. The one-dimensional distances are defined asthe distance between the two atoms at both ends of the arrows except forFIG. 11A in which the distance is defined between the oxygen atom ofwater and the center-of-mass of the protein that lies along thedirection of the arrow. The orientation of the water is fixed as itmoves along the one-dimensional straight path to generate potentialenergies as a function of distance.

The ab initio calculation is performed using Gaussian98 package. Quantumchemistry calculations were performed at several levels of theory, i.e.,HF, DFT/B3LYP and MP2. FIGS. 12A-D shows calculated 1D potential curvescorresponding to the four different interaction paths illustrated inFIGS. 11A-D. For comparison, the corresponding potential curvesgenerated from AMBER force field were plotted in FIGS. 12A-D. FIG. 12Ashows the potential curve obtained by HF/3-21G calculation in which thex-coordinate is defined as the distance between the oxygen atom of thewater and the center-of-mass of gp41 (shown in FIG. 11A). Comparison ofthe ab initio potential curve with that from the force field in FIG. 12Ashows that there are apparent differences between the two potentialcurves. The minimum position given by the force field is shifted outwardby about 0.3 Å in addition to some quantitative difference in energyscales. However, the HF/3-21G level of ab initio calculation employs asmall basis size and include no electron correlation. While HF/3-21 Gtypically gives good equilibrium geometry, its calculated energy may notbe very accurate, as is well known to those in the field.

TABLE 1 Calculated HIV-1 gp41-water interaction energies (kcal/mol) atminimum positions in FIG. 12B and FIG. 12D using different quantumchemistry methods as well as the AMBER force field. Methods 2.85 Å^(b)2.00 Å^(d) 6.30 Å^(d) Amber −3.54 −2.44 −4.35 HF/3-21G −13.91 −7.28−5.27 HF/6-31G −7.78 B3LYP/6-31G −11.77 −6.27 −6.31 MP2/6-31G −10.48−4.63 −6.36 ^(b)Refers to the minimum position FIG. 12B. ^(d)Refers tothe minimum positions in FIG. 12D.

FIG. 12B shows another computed potential curve corresponding to theinteraction path depicted in FIG. 11B. Here four different levels ofcalculations were employed: HF/3-21G, HF/6-31G, B3YLP/6-31G andMP2/6-31G. These calculations show that the HF/3-21G result gives ratheraccurate equilibrium positions but tends to overestimate the hydrogenbonding strength to some extent. In comparison, the HF/6-31G calculationgives bonding energy that seem to be too small. The more accuratecalculation with B3LYP/6-31G, which includes electron correlation, givesbonding energy about 2 kcal/mol smaller than the HF/3-21G result and 4kcal/mol larger than the HF/6-31G result (see Table 1). The MP2calculation, also with 6-31G basis set, gives bonding energy about 1.3kcal/mol smaller than the B3LYP energy. Based on conventional wisdom,the MP2 result is expected to be more reliable and trustworthy.

The force field gives good equilibrium position in FIG. 12B, but itgives bonding energy which is about 7 kcal/mol smaller than the MP2energy. A similar result is seen in FIG. 12C corresponding to theinteraction path shown in FIG. 11C. Here, the force field gives similarequilibrium position but underestimates the strength of hydrogenbonding, while the HF/3-21G is supposed to overestimate the bondingenergy on the comparison in FIG. 12B.

FIG. 12D shows the computed potential curve corresponding to theinteraction path illustrated in FIG. 11D. As shown, this potential curvehas two wells. The HF/3-21G calculation, while giving excellentpositions of the wells, gives a inner well about 2 kcal/mol below theouter well (see Table 1). The B3LYP/6-31G calculation gives two welldepths that are almost equal as can be seen in FIG. 12D and more clearlyin Table 1. In comparison, the MP2/6-31G calculation, which is supposedto be more reliable, gives essentially the same well depth as the B3LYPcalculation for the outer well. However, its calculated well depth forthe inner well is about 1.6 kcal/mol above that of the B3LYP result asshown in Table 1 and in FIG. 12D. FIG. 12D also demonstrates thatoverall, the force field can qualitatively describe the interactionpotential but not in a quantitative fashion.

The MFCC method is particularly suited for ab initio calculation ofprotein-drug interaction. Currently existing docking programs that playimportant roles in fast screening of drug candidates rely almostexclusively on empirical molecular force fields to obtain interactionenergies. The MFCC method makes full quantum mechanical or ab initiocalculation of targeted protein-inhibitor interaction possible andcomputationally practical. This could lead to a quantum jump in theunderstanding, prediction, and design of protein inhibitors in drugdiscovery and in other areas of chemical biology.

The computational cost is reduced using the MFCC method. In thenumerical test, such as that performed in FIGS. 9A-F, a single pointMFCC calculation using HF/3-21G method for the Gly-Ser-Ala-Asp-Val/waterinteraction system (with 62 atoms) takes about 2 minutes on a singleprocessor Intel Pentium 1.5 GH linux workstation. In FIGS. 11A-D, asingle-point energy calculation of the gp41-water interaction system(with 985 atoms) at the HF/3-21G level takes about 67 minutes on aPentium 1.5 GH PC running linux. With respect to correlated methods, thecorresponding single point calculation takes about 516 and 518 minutes,respectively, using B3LYP/6-31G and MP2/6-31G methods. In fact, the MP2calculation does not take as much time as had been expected for largesystems simply because each individual MP2 calculation involving aprotein fragment is still relatively small despite the large size of theprotein. This demonstrates that one could actually employ high levelelectron correlation methods to do practical calculations forprotein-molecule interaction energies beyond HF and DFT methods.

Because the computational cost of the MFCC method is linearlyproportional to the number of amino acids, the ab initio calculationsmay be extended straight to molecular interaction with real proteinmolecules with hundreds of amino acids. Thus the MFCC method makes fullab initio calculation of protein-molecular interaction energy practicaleven on personal computers. The ab initio calculation of the MFCC methodcan be easily parallelized to run on multi-node computer clusters inwhich individual fragments can be calculated simultaneously on separatecomputers. This can dramatically speed up the computation. For example,ab initio MFCC calculation for molecular interaction with a 200-residueprotein on a 100-node clusters would take about the same amount of timeas the that for molecular interaction with a 2-residue peptide on asingle-node computer.

Full ab initio computation of interaction energies between a firstmolecule, such as a protein, and a second molecule, such as a watermolecule, in which the entire system is included in the quantummechanical treatment represents a new benchmark in extending quantummechanical study to biological molecules.

The MFCC scheme is of particular relevance to the quantum mechanicalcalculations of protein-drug interactions. The process has been appliedto the calculation for streptavidin-biotin binding complex and has beenused to design a compound that shows better binding to HIV-1 RT than theFDA-approved drug Nevirapine.

1. A computer-based method of calculating an intermolecular interactionenergy between two molecules, comprising the steps of: providing a firstmolecule; decomposing the molecule into two or more molecular fragments;introducing one or more pairs of conjugate caps having a first capmember and a second cap member at each decomposition point of themolecular fragments to create a plurality of molecular portions, whereineach molecular portion comprises a fragment of the first molecule and atleast one cap member; coupling each pair of conjugate caps to form oneor more coupled caps; determining the interaction energies (a) betweeneach molecular portion and a second molecule, and (b) between each pairof coupled caps and the second molecule; using a computer processor,calculating an intermolecular interaction energy between the firstmolecule and the second molecule based on the interaction energydeterminations; and displaying the results of the calculatedintermolecular interaction energy.
 2. The method as set forth in claim1, wherein the first molecule is provided by electronically generating arepresentation of a physical molecule.
 3. The method as set forth inclaim 2, wherein the decomposing step comprises electronically cuttingthe representation of the molecule.
 4. The method as set forth in claim3, wherein the introducing step comprises electronically introducing theone or more pairs of caps into the electronically generated firstmolecule.
 5. The method as set forth in claim 1, wherein the step ofdetermining interaction energy between the molecular portions and thesecond molecule comprises calculating an interaction energy between afirst molecular portion and the second molecule on a first computingsystem, and calculating the interaction energy between a secondmolecular portion and the second molecule on a second computing system.6. The method as set forth in claim 1, wherein the calculating stepcomprises summing together the interaction energies determined for eachof the molecular portions and the second molecule to provide a totalinteraction energy of the molecular portions.
 7. The method as set forthin claim 6, wherein the calculating step comprises summing together theconjugated cap interaction energies determined from each pair of coupledcaps and the second molecule to provide a total conjugated capinteraction energy; and subtracting the total conjugated cap interactionenergy from the total interaction energy of the molecular portions. 8.The method as set forth in claim 7, wherein the intermolecularinteraction energy is a quantum mechanical intermolecular interactionenergy.
 9. The method as set forth in claim 1, wherein the firstmolecule is a polyatomic species.
 10. The method as set forth in claim9, wherein the polyatomic species is selected from the group consistingof, a protein, a peptide, a polymer, DNA, and RNA.
 11. The method as setforth in claim 1, wherein the second molecule is selected from the groupconsisting of an ion, a water molecule, an inorganic molecule, anorganic molecule, a drug molecule, and a biological molecule.
 12. Themethod as set forth in claim 1, wherein the first molecule is a proteinor a peptide and the second molecule is a drug molecule.
 13. The methodas set forth in claim 1, wherein the first and second cap members areindependently selected from the group consisting of NH₂, HNCOH, CH₃,CRH₂, CRHCOH, CRHCONH₂, CRHNH₂, CRHNHCOH, COH, and CONH₂, wherein R is acarbon-containing group.
 14. A non-transitory computer-readable storage;medium having stored thereon computer-executable instructions forcalculating an intermolecular interaction energy, said instructionscomprising: computer-executable instructions for providing a firstmolecule; computer-executable instructions for decomposing the firstmolecule into two or more molecular fragments; computer-executableinstructions for introducing one or more pairs of conjugate caps havinga first cap member and a second cap member at each decomposition pointof the molecular fragments to create a plurality of molecular portions,wherein each molecular portion comprises a fragment of the firstmolecule and at least one cap member; computer-executable instructionsfor coupling each pair of conjugate caps to form one or more coupledcaps; computer-executable instructions for determining the interactionenergies (a) between each molecular portion and a second molecule, and(b) between each pair of coupled caps and the second molecule;computer-executable instructions for calculating an intermolecularinteraction energy between the first molecule and the second moleculebased on the interaction energy determinations; and computer-executableinstructions for displaying the results of the calculated intermolecularinteraction energy; wherein the computer-readable medium is a physicalmedium.
 15. The medium as set forth in claim 14, wherein thecomputer-executable instructions for calculating an intermolecularinteraction energy comprise computer-executable instructions for summingtogether the interaction energies determined for each of the molecularportions and the second molecule to provide a total interaction energyof the molecular portions.
 16. The medium as set forth in claim 15,wherein the computer-executable instructions for calculating anintermolecular interaction energy comprise computer-executableinstructions for summing together the conjugated cap interactionenergies determined from each pair of coupled caps and the secondmolecule to calculate a total conjugated cap interaction energy; andcomputer-executable instructions for subtracting the total conjugatedcap interaction energy from the total interaction energy of themolecular portions to calculate the intermolecular interaction energybetween the first molecule and the second molecule.
 17. The medium asset forth in claim 16, wherein the intermolecular interaction energy isa quantum mechanical intermolecular interaction energy.
 18. The mediumas set forth in claim 14, wherein the first molecule is a polyatomicspecies.
 19. The medium as set forth in claim 18, wherein the polyatomicspecies is selected from the group consisting of a material, a protein,a peptide, a polymer, DNA, and RNA.
 20. The medium as set forth in claim14, wherein the second molecule is selected from the group consisting ofan ion, a water molecule, an inorganic molecule, an organic molecule, adrug molecule, and a biological molecule.
 21. The medium as set forth inclaim 14, wherein the first and second cap members are selected from thegroup consisting of NH₂, HNCOH, CH₃, CRH₂, CRHCOH, CRHCONH₂, CRHNH₂,CRHNHCOH, COH, and CONH₂, wherein R is a carbon-containing group.
 22. Acomputer system for calculating an intermolecular interaction energy,the system comprising: a processor; a molecular generation module thatprovides a first molecule; a molecular decomposition module thatdecomposes the molecule into two or more molecular fragments; and amolecular cap introduction module that introduces one or more pairs ofconjugate caps having a first cap member and a second cap member at eachdecomposition point of the molecular fragments to create a plurality ofmolecular portions, wherein each molecular portion comprises a fragmentof the first molecule and at least one cap member; a coupling modulethat couples each pair of conjugate caps to form one or more coupledcaps; an interaction energy module that determines the interactionenergies (a) between each molecular portion and a second molecule, and(b) between each pair of coupled caps and the second molecule; anintermolecular interaction energy module that calculates anintermolecular interaction energy between the first molecule and thesecond molecule based on the interaction energy determinations; and adisplaying module that displays the results of the calculatedintermolecular interaction energy.
 23. The system as set forth in claim22, wherein the interaction energy module comprises at least one firstcomputing system that determines an interaction energy between a firstmolecular portion and the second molecule, and at least one secondcomputing system that determines an interaction energy between a secondmolecular portion and the second molecule.
 24. The system as set forthin claim 22, wherein the intermolecular interaction energy module sumstogether the interaction energies determined for each of the molecularportions and the second molecule to provide a total interaction energyof the molecular portions.
 25. The system as set forth in claim 24,wherein the intermolecular interaction energy module sums together theconjugated cap interaction energies determined from each pair of coupledcaps and the second molecule to provide a total conjugated capinteraction energy; and subtracts the total conjugated cap interactionenergy from the total interaction energy of the molecular portions tocalculate the intermolecular interaction energy between the firstmolecule and the second molecule.
 26. The system as set forth in claim25, wherein the intermolecular interaction energy is a quantummechanical intermolecular interaction energy.
 27. The system as setforth in claim 22, wherein the first molecule is a polyatomic species.28. The system as set forth in claim 27, wherein the polyatomic speciesis selected from the group consisting of, a protein, a peptide, apolymer, DNA, and RNA.
 29. The system as set forth in claim 22, whereinthe second molecule is selected from the group consisting of an ion, awater molecule, an inorganic molecule, an organic molecule, a drugmolecule, and a biological molecule.
 30. The system as set forth inclaim 22, wherein the first molecule is a protein or a peptide and thesecond molecule is water.
 31. The system as set forth in claim 22,wherein the first and second cap members are selected from the groupconsisting of NH₂, HNCOH, CH₃, CRH₂, CRHCOH, CRHCONH₂, CRHNH₂, CRHNHCOH,COH, and CONH₂, wherein R is a carbon-containing group.